Oral formulation

ABSTRACT

The present invention relates to a pharmaceutical composition, in particular to a composition for administering active agents which are poorly soluble in aqueous media, and/or which are acid sensitive.

[0001] The present invention relates to a pharmaceutical composition, inparticular to a composition for administering active agents which arepoorly soluble in aqueous media and/or which are acid sensitive. Moreparticularly, the present invention relates to a pharmaceuticalcomposition for administering active agents acting on thegastro-intestinal system. The present invention also relates to aprocess for manufacturing such compositions. The term “pharmaceutical”also covers veterinary use.

[0002] Pharmaceutical compositions containing active agents which arepoorly soluble in aqueous media and/or acid sensitive are difficult tomanufacture. One of the problems that may occur concerns adsorption ofthe active agent on the process equipment during the manufacturingprocess. Due to the poor solubility of such active agents it is alsodifficult to obtain pharmaceutical compositions which uponadministration have a good dissolution rate. As a further problem,active agents may be degraded, e.g., chemically, during a manufacturingprocess using acidic conditions or during the storage of thecomposition.

[0003] The present invention provides compositions and processes whichavoids or minimise one or more of the above problems.

[0004] We have now surprisingly found that it is possible to produce apharmaceutical composition for administering of active agents which arepoorly soluble in aqueous media, e.g., pure water, and/or acidsensitive, and which upon administration has good dissolutionproperties, a good bioavailability and is surprisingly efficacious.

[0005] The present invention provides in one aspect a solid oralpharmaceutical composition, e.g., a tablet, comprising an active agentwhich is poorly soluble in aqueous media, and/or acid sensitive, and adisintegrant, e.g., a super-disintegrant, which is present in an amountof at least 15% by weight based on the total weight of the composition.

[0006] By “poorly soluble” is meant an active agent having a solubilityin aqueous media more than 0.001% and less than 10%, e.g., less than 1%,e.g., less than 0.1%, e.g., less than 0.05%, e.g., less than 0.02%, atroom temperature, e.g., 25° C.

[0007] By “acid sensitive” is meant an active agent which under evenslightly acidic conditions, e.g., at pH 6, may be transformed to asignificant extent in a degradation product, e.g., by chemicaldegradation, which may have no or changed activity, e.g., within 2hours. Examples of compounds are known in the art and may be ascertainedby routine experimentation.

[0008] By “disintegrant” is meant a substance or mixture of substanceadded to a solid pharmaceutical composition, e.g., a tablet, tofacilitate its break-up or disintegration after administration in orderthat the active ingredient is released from the composition asefficiently as possible to allow for its rapid dissolution (see e.g.“Remington's Pharmaceutical Science” 18th edition (1990), “The Theoryand Practice of Industrial Pharmacy” Lachman et al. Lea & Febiger(1970)).

[0009] We have also found difficulties on producing stable commerciallyacceptable formulations, e.g., tablets, of compounds such as thosedisclosed in EP505322 (herein incorporated by reference) and which areuseful as 5-HT₄ receptor agonists or partial agonists.

[0010] A preferred 5-HT₄ partial agonist disclosed in EP505322 isTegaserod(3-(5-methoxy-1H-indol-3-yl-methylene)-N-pentylcarbazimidamide) (example13) of formula

[0011] which is referred hereinafter as Compound A, or apharmaceutically acceptable salt form thereof, e.g., the hydrogenmaleate (hereinafter “hml”) salt. Compound A has a solubility of about0.02% at 25° C. in water and is acid sensitive. We have found thatcompositions may be produced which give good absorption even in thestomach. We have also found that Compound A may be adsorbed by certainexcipients so that its dissolution upon administration may besubstantially reduced.

[0012] Little has been published in detail on 5-HT₄ receptor agonists,partial agonists or antagonists biopharmaceutical properties, e.g.,their site of action is not known.

[0013] The present invention provides in a further aspect pharmaceuticalcompositions allowing a complete dissolution of 5-HT₄ receptor agonists,partial agonists or antagonists, e.g., Compound A, when administered tohumans, e.g., patients, in need thereof. These compositions allow a goodbioavailability and are surprisingly efficacious. Moreover, they arestable and well reproducible. A process for their preparation is alsoprovided.

[0014] Active agents which may be used in compositions according to thepresent invention are more generally those acting on thegastro-intestinal system, e.g., serotonergic active agents, e.g., fullagonists, partial agonists and antagonists of 5-HT₄ receptors to theextent they are poorly soluble and/or acid sensitive. They arepreferably in salt form, e.g., hydrogen maleate or hydrochloride, andmay be in free form.

[0015] The 5-HT₄ receptor is a cloned species of the serotonin receptorfamily which comprises at least 14 distinct G protein-coupled receptors(the receptor ionophore of the 5-HT₃ subtype excluded). Four splicevariants of the human receptor, 5-HT_(4A), 5-HT_(4B), 5-HT_(4C), and5-HT_(4D), have been identified which differ in the length and sequenceof the protein's C terminus (Blondel et al., FEBS Letters (1997)412:465-474; Blondel et al., J. Neurochem. (1998) 70: 2252-2261).Biochemical characterisation of 5-HT₄ receptors revealed a positivecoupling to adenylyl cyclase. 5-HT₄ receptor expression in man has beenfound in the brain, the gut, the atria, the urinary bladder and kidneys.

[0016] Compounds capable of acting on the serotonin receptor aresubstituted benzamides, e.g., cisapride, renzapride, zacopride,clebopride, cinitapride, mosapride, lintopride, metoclopramide, orbenzoic esters, e.g., RS 23597-190, SB 204070, SB 207710, oraminoguanidines, zacopride, prucalopride, SB 205149, SC 53116, RS 67333,RS 67506, BIMU 1, BMIU 8, (S)-RS 56532, Tropisetron, Alosetron, GR113808, GR 125487, SB 207266, RS 23597, RS 39604, RS 100235, DAU 6285,SC 53606,3-(5-hydroxy-7-methyl-1H-indol-3-yl-methylene)-N-pentyl-N-methyl-carbazimidamide,indazole-3-carboxamides, 2-oxobenzamidazole-3-carboxamides (as disclosedin EP 908 459 which is herein incorporated by reference) etc.

[0017] 5-HT₄ receptor agonists are considered as compounds which canactivate 5-HT₄ receptors under quiescent/resting conditions (complete orpartial activation). As 5-HT₄ receptor full agonists or partial agonistsone may cite (S)-zacopride, cisapride, prucalopride, SB 205149, SC53116, RS 67333, RS 67506, BIMU 1, BIMU 8, (S)-RS 56532 and Compound A,particularly its hydrogen maleate salt.

[0018] 5-HT₄ receptor antagonists are considered as compounds which donot activate 5-HT₄ receptors but act as inhibitors of agonists at 5-HT₄receptors. As 5-HT₄ receptor antagonists one may cite GR 113808, GR125487, SB 203186, SB 204070, SB 207266, RS 23597, RS 39604, RS 100235,DAU 6285, SC 53606,3-(5-hydroxy-7-methyl-1H-indol-3-yl-methylene)-N-pentyl-N-methyl-carbazimidamide.

[0019] 5-HT₄ receptor agonists are useful for the prevention andtreatment of gastro-intestinal motility disorders, e.g., Irritable BowelSyndrome (IBS), Gastro-Esophageal Reflux Disease (GERD), FunctionalDyspepsia (FD) and Post Operative Ileus (POI).

[0020] In a preferred embodiment, the composition of the inventioncomprises 20 to 60%, e.g., 30 to 50%, e.g. 40% by weight of disintegrantbased on the total weight of the composition. We have observed that theuse of such a high percentage of disintegrant further improves thedissolution rate in aqueous media, but also prevents the active agentfrom adsorbing on excipients.

[0021] As disintegrants the composition of the invention may comprise:

[0022] crospovidone (molecular weight>10⁶), e.g., Polyplasdone XL®,Kollidon CL®, Polyplasdone XL-10®,

[0023] pregelatinised starch (MW: 30 000-120 000), e.g., starch 1500®,STA-Rx 1500®,

[0024] sodium starch glycolate (MW: 500 000-1 000 000), e.g. Primojel®,

[0025] carboxymethylcellulose calcium (CMC-Ca),

[0026] carboxymethylcellulose sodium (CMC-Na) (MW: 90 000-700 000),e.g., Ac-Di-Sol®,

[0027] sodium alginate,

[0028] or a mixture thereof.

[0029] Preferably, the disintegrant is crospovidone which is preferablywater insoluble. Preferably it rapidly exhibits high capillary orpronounced hydration capacity with little tendency to gel formation.Preferably the particle size is from about 1 to 500 micrometers.Preferred particle size distribution is less than 400 micrometers, e.g.,for Polyplasdone XL®, less than 80 micrometers, e.g., less than 74micrometers for, e.g., Polyplasdone XL-10®, approximately 50% greaterthan 50 micrometers and maximum of 1% greater than 250 micrometers insize for, e.g., Kollidon CL®. A preferred crospovidone is PolyplasdoneXL®, e.g., with a density of about 0.213 g/cm³ (bulk) or 0.273 g/cm³(tapped).

[0030] The pharmaceutical composition of the invention may furthercomprise one or more excipients.

[0031] The composition may further comprise one or more lubricants,e.g., in an amount within the range of from, e.g., 1 to 20%, e.g., from5 to 15%, e.g., 10% by weight of the composition.

[0032] Examples of such lubricants include

[0033] glyceryl mono fatty acid, e.g., having a molecular weight of from200 to 800, e.g., glyceryl monostearate (e.g., Myvaplex®, USP quality)

[0034] polyethylene glycol (PEG), having a molecular weight of from 100to 10000, e.g., 1000 to 8000, e.g., 2000 to 6000, e.g., 2500 to 5000,e.g., Macrogol 4000 (Pulver) BP,

[0035] hydrogenated castor oil (e.g., Cutina), and the like

[0036] or a mixture thereof.

[0037] In a preferred composition the lubricant is glycerylmonostearate. The lubricant properties of such preferred composition maybe improved by adding polyethylene glycol (PEG), e.g., Macrogol 4000(Pulver) BP.

[0038] The composition of the invention may comprise one or moresurfactants, e.g., in an amount in the range of from 0.1 to 10%, e.g., 1to 5%, e.g. 2% by weight of the total composition. Pharmaceuticallysuitable surfactants may be non-ionic or anionic.

[0039] As non-ionic surfactants one may use:

[0040] polyoxyethylene-sorbitan-fatty acid esters (polysorbates; MW: 500to 2000), e.g., mono- and tri-lauryl, palmityl, stearyl and oleylesters, e.g., Tween®, e.g., Tween 80®;

[0041] polyoxyethylene fatty acid esters (MW: 500 to 5000), e.g., Myrj®or Cetiol®;

[0042] polyoxyethylene-polyoxypropylene co-polymers, e.g., having amolecular weight of from 1000 to 20 000, e.g., 6 000 to 15 000, e.g., 7000 to 10 000, e.g., Pluronic® or Emkalyx®;

[0043] polyoxyethylene-polyoxypropylene block co-polymers e.g., having amolecular weight of from 1000 to 20 000, e.g., 6 000 to 15 000, e.g., 7000 to 10 000, e.g., Poloxamer 188®;

[0044] reaction products of a natural or hydrogenated castor oil andethylene oxide, e.g., Cremophor®;

[0045] dioctylsuccinate or di-[2-ethylhexyl]-succinate;

[0046] propyleneglycol mono- and di-fatty acid (e.g. C₆-C₈) esters,e.g., Miglyol®;

[0047] or mixtures thereof.

[0048] As suitable anionic surfactants one may use, e.g., sodiumlaurylsulfate or docusate sodium.

[0049] Unless where otherwise stated fatty acid or carbon containingchain is from about 8 to 22 carbon atoms, e.g., C₁₈.

[0050] The composition of the invention may comprise one or morebinders, e.g., in an amount in the range of from 1 to 10%, e.g., 2 to8%, e.g., 5% by weight. One may particularly use:

[0051] hydroxypropylmethylcellulose, e.g., having a molecular weight offrom 10 000 to 1 500 000, e.g., HPMC-3 (3mPa-s) (e.g. Pharmacoat®,Methocel®),

[0052] polyvinylpyrrolidone, e.g., having a molecular weight of from2500 to 3 000 000, e.g., 8 000 to 1 000 000, e.g., 10 000 to 400 000,e.g., 30 000 to 50 000 (e.g., Kollidon®, Plasdone®),

[0053] potato starch, wheat starch, corn starch, e.g., having amolecular weight of from 30 000 to 120 000,

[0054] or a mixture thereof.

[0055] The composition of the invention may comprise one or morediluents such as lactose, mannitol, sucrose, calcium sulphate, calciumphosphate, microcristalline cellulose (Avicel®) in an amount within therange of from, e.g., 10 to 70%, e.g., 20 to 50%, e.g., 30% by weight ofthe composition. Preferably, the diluent is lactose, e.g., lactose 200mesh (e.g., from DMV® or Alpavit®), e.g., the monohydrated form.

[0056] Other conventional excipients which may optionally be present inthe composition of the invention include preservatives, stabilisers,anti-adherents or silica flow conditioners or glidants, e.g., silicondioxide (e.g., Syloid®, Aerosil®) as well as FD&C colours such as ferricoxides.

[0057] Other excipients disclosed in the literature, as for instance inFiedler's “Lexicon der Hilfstoffe”, 4th Edition, ECV Aulendorf 1996 and“Handbook of Pharmaceutical Excipients” Wade and Weller Ed. (1994), thecontents of which are incorporated herein by reference, may be used inthe pharmaceutical compositions according to the invention.

[0058] The invention is particularly useful for pharmaceuticalcompositions containing an active agent, e.g., an 5HT₄ receptor agonist,partial agonist or antagonist, e.g., compound A, e.g., the hydrogenmaleate salt, which is present in an amount within the range of fromabout 0.2% to about 20%, e.g. 0.5 to 15%, and preferably from about 1%to about 10% by weight of the composition.

[0059] A preferred composition of the invention may comprise from about0.5 to about 15% by weight of active agent, e.g., a 5HT₄ receptoragonist, e.g., compound A, e.g., the hydrogen maleate salt, from 20 to60% by weight of disintegrant, e.g., crospovidone, from 1 to about 20%by weight of a lubricant, e.g., monoglycerylstearate, from 0.1 to about10% by weight of a surfactant, e.g., poloxalkol, from about 10 to 50% byweight of a diluent, e.g., lactose, and from 1 to 10% by weight of abinder, e.g., hydroxypropylmethyl cellulose (e.g. HPMC-3). From 1 to 10%by weight of PEG may also be added.

[0060] The weight ratio of the active agent to the disintegrant may befrom 1:1 to 1:400, e.g., 1:5 to 1:100, 1:8 to 1:50, e.g., 1:16 to 1:20.

[0061] In a further aspect the present invention provides apharmaceutical oral, e.g., tablet, composition comprising one of theactive agents cited above, e.g., a 5-HT₄ agonist, partial agonist orantagonist, e.g., Tegaserod, said composition having dissolutioncharacteristics in water or in USP buffers pH 6.8 and 7.5 of: time(minutes) amount (percentage) 5 30-90 15  80-100 30  95-100 60 100

[0062] According to the invention, e.g., comprising Tegaserod as theactive agent, may have dissolution characteristics in water or in USPbuffers pH 6.8 and 7.5 of: time (minutes) amount (percentage) 5 48.9 1595.5 30 99.7 60 100

[0063] In a further aspect the present invention provides apharmaceutical oral, e.g., tablet, compoisition comprising one of theactive agents cited above, e.g., a 5-HT₄ agonist, partial agonist orantagonist, e.g., Tegaserod, wherein in use 80% of said active agent isreleased in water or on USP buffers pH 6.8 and 7.5 within 5 minutes.

[0064] In a further aspect, the present invention provides the use of atleast 15% by weight of a disintegrant in the manufacturing ofpharmaceutical composition for the administration of an acid sensitiveand/or poorly soluble, e.g., in aqueous media, active agent, e.g., a5-HT₄ receptor agonist, e.g., compound A, e.g. the hydrogen maleatesalt.

[0065] The pharmaceutical compositions of the present invention areuseful in the known indications of the particular active agentincorporated therein.

[0066] The exact amounts of the active agent and of the formulation tobe administered depend on a number of factors, e.g. the condition to betreated, the desired duration of treatment and the rate of release ofactive agent.

[0067] For example. the amount of the active agent required and therelease rate thereof may be determined on the basis of conventional invitro or in vivo techniques, determining how long a particular activeagent concentration in the blood plasma remains at an acceptable levelfor a therapeutic effect.

[0068] Examples of doses provided in a solid formulation, e.g., atablet, are, for Irritable Bowel Syndrome (IBS), 1 mg to 12 mg of activeagent, for functional dyspepsia (FD) and gastroesophageal reflux disease(GERD), 0.2 to 2 mg of active agent, in particular compound A, e.g. thehydrogen maleate salt, per day for a 70 kilogram mammal, e.g. humans,and in standard animal models. The increased tolerability of the activeagent, in particular compound A, e.g. the hydrogen maleate salt,provided by the compositions may be observed in standard animal testsand in clinical trials.

[0069] The pharmaceutical composition of the invention comprising a5-HT₄ receptor agonist, partial agonist or antagonist is particularlyuseful for improving sensory perception of rectal distension, e.g. forthe treatment of anal incontinence, or for preventing, modulating ortreating visceral pain or discomfort.

[0070] 5-HT₄ receptor agonists, partial agonists or antagonists, e.g. asdisclosed in EP-A1-505,322, on the basis of observed activity, e.g.stimulatory effect on the peristaltic reflex in the isolated guinea-pigileum, e.g. as described in EP-A1-505,322, have been found to be usefulfor the treatment of gastro-intestinal motility disorders, for exampleto normalise or to improve the gastric emptying and intestinal transitin subjects having a disturbed motility, e.g. in irritable bowelsyndrome.

[0071] In accordance with the present invention, it has now surprisinglybeen found that 5-HT₄ receptor agonists, partial agonists or antagonistshave a beneficial effect, e.g. they exert modulating effects, on thesensory perception of rectal distension and on visceral sensitivity orperception.

[0072] It is admitted that receptor properties are not uniformthroughout the gut and that the type of afferent innervation reflectsthe quality of sensations originating from a particular organ. Forexample, the rectum belongs to those parts of the gastro-intestinaltract from which also non-painful sensations arise, in contrast to thecolon from which only painful sensations emanate.

[0073] Anal incontinence may be due to functional disturbances of themain anal continence mechanisms. Anal continence appears to be based ona coordinated functioning of the neuromuscular machinery managing rectalsensation and compliance, the recto-anal inhibitory reflex, reflexcontractions of the external anal sphincter and the puborectalis muscle.Although skeletal muscle (external sphincter and puborectalis)contractions are of great importance in the maintenance of continence,it is probably the triggering effect of rectal sensation and perceptionthat plays a crucial role and, in fact, is frequently abnormal inincontinent patients. Anal incontinence is a dysfunction which occursparticularly in diabetics and the elderly population.

[0074] There is a medical need for modulating visceral sensitivity,discomfort or pain in patients suffering from gastro-intestinaldisorders and for a treatment of anal continence dysfunctions.

[0075] In accordance with the particular findings of the presentinvention, there is provided:

[0076] 1.1. A method for preventing, modulating or treating visceral,e.g. abdominal, pain or discomfort in a subject in need thereof, whichmethod comprises administering to said subject an effective amount of a5-HT₄ receptor agonist, partial agonist or antagonist or apharmaceutically acceptable salt thereof.

[0077] 1.2. A method for modulating visceral sensitivity or perceptionin a subject in need thereof, which method comprises administering tosaid subject an effective amount of a 5-HT₄ receptor agonist, partialagonist or antagonist or a pharmaceutically acceptable salt thereof.

[0078] 1.3. A method for stimulating 5-HT₄ receptors present on afferentnerve terminals, particularly on extrinsic neurones of the gut, in asubject in need thereof, which method comprises administering to saidsubject an effective amount of a 5-HT₄ receptor agonist or partialagonist or a pharmaceutically acceptable salt thereof.

[0079] 1.4. A method for modulating visceral sensitivity, discomfort orpain via stimulation of 5-HT₄ receptors present on afferent nerveterminals, particularly on extrinsic neurones of the gut, in a subjectin need thereof, which method comprises administering to said subject aneffective amount of a 5-HT₄ receptor agonist or partial agonist or apharmaceutically acceptable salt thereof.

[0080] 1.5. A method for regulating or stabilising myentericplexus-afferent fibbers in a subject in need thereof, which methodcomprises administering to said subject an effective amount of a 5-HT₄receptor agonist or partial agonist or a pharmaceutically acceptablesalt thereof.

[0081] 1.6. A method for improving sensory perception of rectaldistension in a subject in need thereof, which method comprisesadministering to said subject an effective amount of a 5-HT₄ receptoragonist, partial agonist or antagonist or a pharmaceutically acceptablesalt thereof.

[0082] 1.7. A method for treating anal continence dysfunctions in asubject in need thereof, which method comprises administering to saidsubject an effective amount of 5-HT₄ receptor agonist, partial agonistor antagonist or a pharmaceutically acceptable salt thereof.

[0083] As alternative to the above the present invention also provides:

[0084] 2. A 5-HT₄ receptor agonist, partial agonist or antagonist or apharmaceutically acceptable salt thereof for use in a method as definedunder 1.1 to 1.7 above; or

[0085] 3. A 5-HT₄ receptor agonist, partial agonist or antagonist or apharmaceutically acceptable salt thereof for use in the manufacture of apharmaceutical composition for use in a method as defined under 1.1 to1.7 above; or

[0086] 4. A pharmaceutical composition for use in a method as definedunder 1.1 to 1.7 above comprising a 5-HT₄ receptor agonist, partialagonist or antagonist or a pharmaceutically acceptable salt thereof,together with one or more pharmaceutically acceptable diluents orcarriers therefor, e.g. a composition such as disclosed hereinabove.

[0087] Preferred compounds for use in accordance with the inventioninclude e.g. those listed hereinabove, particularly 5-HT₄ receptor fullagonists or partial agonists, e.g. (S)-zacopride, cisapride,prucalopride, SB 205149, SC 53116, RS 67333, RS 67506, BIMU 1, BIMU 8,(S)-RS 56532, especially Compound A and particularly its hydrogenmaleate salt, more preferably selective 5-HT₄ receptor agonists orpartial agonists, and 5-HT₄ receptor antagonists, e.g. Tropisetron, GR113808, GR 125487, SB 204070, SB 207266, RS 23597, RS 39604, RS 100235,DAU 6285, SC 53606,3-(5-hydroxy-7-methyl-1H-indol-3-yl-methylene)-N-pentyl-N-methyl-carbazimidamideetc. By selective is meant a compound which does not substantially bindto or stimulate the serotonin 5-HT₃ receptor. A group of compoundsexcludes Tropisetron.

[0088] Utility of a 5-HT₄ receptor agonist, partial agonist orantagonist in the prevention, modulation or treatment of visceral, e.g.,abdominal pain or discomfort or modulation of visceral sensitivity orperception or regulation or stabilisation of myenteric plexus-afferentfibers, is demonstrated in convenient tests, e.g., in accordance withthe method hereinafter described.

[0089] Decerebrate, anaesthesia-free cats under continuous monitoring ofblood pressure are paralysed by alcuronium chloride dissolved inrheomacrodex i.v. (200 μg/kg initially and supplementary doses of 100μg/kg, if necessary), and artificially ventilated. Single unit activityof afferent fibres are recorded in a monopolar fashion from peripheralendings of centrally cut filaments of sacral dorsal roots. Tensionreceptors are identified by probing of their receptive fields in thewall of the mobilised rectum. Thereafter, the response of the units tobarostat-controlled rectal ramp-distension is determined. Thequantitative response characteristics of the units is evaluated withrespect to distension pressure and resulting rectal diameter.Alternatively, the response of the units to pressure-induced peristalsisis measured.

[0090] After obtaining 2 distension profiles (5 min each) and/or 10 minof peristalsis under control conditions, a 5-HT₄ receptor agonist,partial agonist or antagonist, e.g., Compound A, or vehicle is appliedi.v. and the protocol is repeated. Subsequently, the activity ofadditional units is recorded in the presence of a 5-HT₄ receptoragonist, partial agonist or antagonist, e.g., Compound A, or vehicleaccording to the distension/peristalsis protocol. In this assay, thefiring rate of the rectal afferents is reduced after administration of a5-HT₄ receptor agonist or partial agonist at a dose range of from 0.1 to3 mg/kg i.v., at distension pressures above 20 mmHg. With Compound A,administered i.v. in incremental doses from 0.15 to 1.2 mg/kg, the mostprominent inhibition occurs at 50 mmHg and a half-maximal reduction isobtained at about 0.7 mg/kg.

[0091] Utility of a 5-HT₄ receptor agonist, partial agonist orantagonist, e.g., Compound A, in the treatment of anal incontinence aswell as utility in treating conditions as hereinabove specified, may bedemonstrated in accordance with the method hereinafter described.

[0092] Intraluminal pressures and reflexes in the last 60 cm of thecolon of 10 fasted healthy volunteers are measured by means of perfusionmanometry. Three latex balloons positioned at 50, 30 and 10 cm, allowvolume stimulation. Basal values of colonic intraluminal pressures andreflexes are established. Subsequently, reflex inhibitory relaxations ofthe internal anal sphincter is triggered by inflating the balloons by 10ml increments up to a maximum volume of 150 ml. During the inflationphase, two parameters are evaluated: a) the reflux threshold (volumeable to induce a substantial pressure decrease of the internal analsphincter); and b) the sensation threshold (volume able to induce aconscious defecation reflex). After the basal recordings, each subjectis given a 5-HT₄ receptor agonist, partial agonist or antagonist, e.g.,Compound A, p.o. and 30 to 90 min later the colonic intraluminalpressure and reflexes are assessed again by the same method. In thistest, the 5-HT₄ receptor agonist, partial agonist or antagonist, e.g.,Compound A, significantly reduced the sensation threshold whenadministered at a dose of 2-12 mg p.o.

[0093] 5-HT₄ receptor agonists, partial agonists or antagonists, e.g.,Compound A, may be administered by any conventional route, in particularenterally, preferably orally, e.g., in the form of tablets or capsules,or parenterally, e.g., in the form of injectable solutions orsuspensions or in a suppository form.

[0094] 5-HT₄ receptor agonists, partial agonists or antagonists, e.g.,Compound A, may be administered in free form or in pharmaceutically saltform. Such salts exhibit the same order of activity as the 5-HT₄receptor agonists, partial agonists or antagonists in free form.

[0095] Daily dosages required in practising the method of the presentinvention will vary depending upon, for example, the particular compoundemployed, the mode of administration and the severity of the conditionto be treated. An indicated daily dose is in the range of from about0.05 to about 30 mg, e.g., from about 0.05 to about 5 mg for parenteraluse, and of from about 0.1 to about 30 mg for oral use, convenientlyadministered once or in divided dosages 2 to 4×/day, or in sustainedrelease form. Unit dosage forms for oral administration accordinglycomprise from about 0.5 to about 30 mg of 5-HT₄ receptor agonist,partial agonist or antagonist, e.g., Compound A, or a pharmaceuticallyacceptable salt thereof, admixed with an appropriate solid or liquid,pharmaceutically acceptable diluent or carrier therefor.

[0096] Furthermore, it has also been found that a 5-HT₄ receptor agonistor partial agonist—e.g., Compound A, have a beneficial effect in theprevention or treatment of gastro-intestinal motility disorders, e.g. astimulatory effect on gastrointestinal motility, in horses and cattle.

[0097] Accordingly, there is also provided:

[0098] 5.1. A method for preventing or treating gastrointestinalmotility disorders, e.g. by stimulating the motility of thegastrointestinal tract in horses or cattle in need thereof, which methodcomprises administering to the horses or cattle an effective amount of a5-HT₄ receptor agonist or partial agonist, e.g., Compound A, or apharmaceutically acceptable salt thereof.

[0099] 5.2. A method for preventing or treating gastro-intestinalmotility disorders, e.g. after colic surgery, e.g. post-operative Ileus,in horses or cattle in need thereof, which method comprisesadministering to the horses or cattle an effective amount of a 5-HT₄receptor agonist or partial agonist, e.g., Compound A, or apharmaceutically acceptable salt thereof.

[0100] 6. A 5-HT₄ receptor agonist or partial agonist, e.g., Compound A,or a pharmaceutically acceptable salt thereof, for use as a veterinarypharmaceutical e.g. for horses or cattle, e.g. in any of the method 5.1or 5.1 indicated above or for use in the manufacture of a veterinarypharmaceutical e.g. for use in a method as defined under 5.1 or 5.2.

[0101] 7. A pharmaceutical composition for veterinary use, e.g. inhorses or cattle, e.g. in any of the method 5.1. or 5.2. as indicatedabove, comprising a 5-HT₄ receptor agonist or partial agonist, e.g.,Compound A, or a pharmaceutically acceptable salt thereof, together witha pharmaceutically acceptable diluent or carrier therefor, e.g. acomposition as disclosed hereinabove.

[0102] Preferred 5-HT₄ receptor agonists or partial agonists for use inhorses or cattle in accordance with the invention include e.g. thoselisted hereinabove, e.g. (S)-zacopride, prucalopride, SB 205149, SC53116, RS 67333, RS 67506, BIMU 1, BIMU 8, (S)-RS 56532, especiallyCompound A and particularly its hydrogen maleate salt, more preferably aselective 5-HT₄ receptor agonist or partial agonist.

[0103] Utility of a 5-HT₄ receptor agonist or partial agonist, e.g.,Compound A, in the treatment of post-operative leus as well as utilityin treating conditions as hereinabove specified in horses or cattle, maybe demonstrated in accordance with the method hereinafter described.

[0104] 20 horses having colic syndrome are submitted to abdominalsurgery. During surgery supportive therapy is applied to them. At theend of surgery, a specific 5-HT₄ receptor agonist or partial agonist,e.g., Compound A, is administered i.v. or i.m., e.g. at a dose of from0.01 to 10 mg/kg. This dose is repeated every 8 to 24 h untilspontaneous defecation is observed. Gastro-intestinal motility isevaluated based e.g. on the presence or absence of gastric reflux asdetermined by nasogastric intubation, occurrence of borborygmi andtiming of defecation after the first injection of the test compound. Inthis test, the compounds tested, e.g. Compound A, are effective inrestoring normal motility function of the equine intestine.

[0105] Daily dosages required in practising the veterinary method of thepresent invention will vary depending upon, for example, the particularcompound employed, the mode of administration and the severity of thecondition to be treated. An indicated daily dose is in the range of fromabout 0.01 to about 10 mg/kg, e.g., from about 0.05 to about 5 mg/kg forparenteral use, conveniently administered once or in divided dosages 2to 4×/day, or in sustained release form.

[0106] In a further aspect the invention provides a method forpreventing or treating gastro-intestinal motility disorders in asubject, e.g., a human or an animal, in need of such a therapycomprising administering to this subject an effective amount of acomposition according to the present invention.

[0107] In a further aspect the invention a process is provided forimproving dissolution properties in aqueous media of a pharmaceuticalcomposition containing an acid sensitive and/or poorly soluble inaqueous media active agent, e.g., a 5-HT₄ receptor agonist, moreparticularly compound A, e.g. the hydrogen maleate salt.

[0108] The pharmaceutical composition of the invention may be preparedby any conventional method known in the art, e.g., by mixing anappropriate amount of the active agent, e.g., a 5-HT₄ receptor agonist,with at least 15%, e.g., from 20 to 60%, e.g., from 30 to 50%, e.g.,40%, by weight of a disintegrant based on the total weight of thecomposition.

[0109] It is preferred to formulate in solid form, e.g., unit dosageform. Typical form include capsules and preferably compressed forms suchas tablets.

[0110] The pharmaceutical composition according to the invention may beprepared by e.g., a wet, e.g., water based, granulation manufacturingprocess (the process equipment, as glass material, may be pre-treatedwith a siliconizing agent) comprising the successive steps of:

[0111] i) pre-mixing the acid sensitive and/or poorly soluble in wateractive agent, e.g., a 5-HT₄ receptor agonist, e.g., compound A, e.g. thehydrogen maleate salt with 60 to 98% of the diluent, and then sievingthe resulting mixture,

[0112] ii) mixing purified water with the binder in a weight ratio offrom 1:20 to 3:20, and stirring until dissolution,

[0113] iii) adding the surfactant to the solution of ii) and stirringuntil dissolution,

[0114] iv) adding the disintegrant, the remaining diluent and 50 to 70%of the first lubricant to the pre mixture of i) and mixing

[0115] v) wetting the mixture of step iv) with the granulating solutionfrom step iii) while mixing

[0116] vi) granulating the mixture of step v) by mixing,

[0117] vii) drying the granulate to reach a required loss on drying,e.g., for the tabletting mixture

[0118] viii) sizing the granulate by sieving.

[0119] For tablet manufacturing the granulate from viii) is mixed, e.g.,in a free fall mixer, with the rest of the first lubricant and thesecond one to obtain the desired final tabletting mixture which may becompressed into tablets. This may be performed with conventionaltabletting machines on, e.g., a rotary machine, at compression pressuresof, e.g., 2 to 30 KN, e.g. 5 to 27 KN, e.g., 10 to 20 KN (KN=KiloNewtons).

[0120] The composition according to the invention may also be preparedby an alternative wet granulation manufacturing process wherein thepre-mixing and sieving of step i) are not performed. In this case, theactive agent, the disintegrant, the diluent and about 60% of the firstlubricant are pre-blended together and then wetted with the wettingsolution of step iv).

[0121] Compositions comprising any of the above-mentioned active agentsmay be prepared by a process as disclosed above.

[0122] If desired the pharmaceutical compositions of the invention arestored under low relative humidity conditions, e.g., rH (relativehumidity) less than 50%, e.g., below e.g. 30-50%, and at roomtemperature, preferably less than 20° C. The compositions providestorage stable systems. Insignificant degradation is detected afterstorage of up to 1 year at room temperature, e.g., 25° C.

[0123] The compositions of the invention may be packed in conventionalmanner to keep out humidity, e.g., in a blister pack, optionally with adesiccant.

[0124] The compositions of the invention may have a water content offrom 0 to 3% based on the total weight of the composition.

[0125] The present invention relates in a further aspect to acomposition, in particular comprising compound A, as obtained by one ofthe above processes to provide a small, stable form.

EXAMPLES

[0126] The following examples illustrate the manufacturing, on anindustrial scale, of compositions comprising compound A hml using a wetgranulation process as disclosed above.

Example 1

[0127] A 2 mg tablet formulation may be prepared as describedhereinafter.

[0128] a) Preparation of the granulated material

[0129] Premixing step.

[0130] 1. 4.432 kg of compound A hml and 28.688 kg of lactosemonohydrate are mixed with an intensive mixer (Colette Gral® 300 I orFielder®); mixer speed setting: 1; chopper speed setting: 1) forapproximately 1.5 minutes, or with a free fall mixer (Turbula®, Soneco®or Röhnrad®)

[0131] 2. The pre-mixture from step 1 is then sieved (oscillatinggranulator, e.g., Frewitt® or Erweka®; mesh size: 0.8 millimetres).

[0132] 3.The pre-mixture is divided into two portions of 16.560 kg.

[0133] Preparation of the granulating solution

[0134] 4. Approximately 40 kg of purified water are weighed out.

[0135] 5. 3.600 kg of methylhydroxypropylcellulose 3 maps are added tothe purified water from step 4 and this is stirred until dissolution.

[0136] 6. 1.440 kg of poloxamer 188 are added to the solution from step5 while stirring until dissolution.

[0137] Granulating step

[0138] 7. 28.800 kg of crospovidone, 10.080 kg of lactose monohydrateand 4.320 kg of glyceryl monostearate are weighed out.

[0139] 8. One portion of the premixture from step 3 is added to theexcipients from step 7 and this is mixed with the intensive mixer, e.g.,Colette Gral® 300 I or Fielder® (mixer speed setting: 1; chopper speedsetting: 1) for approximately 2 minutes.

[0140] 9. The mixture from step 8 is wetted with the granulatingsolution from step 6 while mixing with the intensive mixer, e.g.,Colette Gral® 300 I or Fielder® (mixer speed setting: 1; chopper speedsetting: 0; pumping rate approximately: 4 kg/minute) for approximately12 minutes.

[0141] 10. Approximately 2 kg of purified water are weighed out.

[0142] 11. The vessel from step 6 is rinsed with the purified water fromstep 10 and this is added to the mixture from step 9 while mixing.

[0143] 12. The mass is granulated by mixing with the intensive mixer,Colette Gral® 300 I or Fielder® (mixer speed setting: 1; chopper speedsetting: 1) for approximately 2.5 minutes.

[0144] Drying step

[0145] 13. The granulate from step 12 is dried in a fluidised air beddrier (e.g., Glatt® or Aeromatic®) for approximately 65 minutes (inletair temperature approximately 70° C.) to reach the required loss ondrying (LOD) for the tabletting mixture, i.e., until LOD≦4.4%.

[0146] 14. The granulate sized by sieving (0.8 millimetres) with anoscillating sieve granulator, e.g., Frewitt® or Erweka®.

[0147] 15. Steps 4 to 14 are repeated with the other portion of step 3.

[0148] b) Preparation of the tabletting mixture

[0149] 16. 8.640 kg of polyethylene glycol 4000 and 5.760 kg of glycerylmonostearate are sieved (oscillating granulator, e.g., Frewitt® orErweka®; mesh size: 0.8 millimetres)

[0150] 17. The ingredients from step 16 are added to the total mass ofgranulated material and this is mixed with a free fall mixer, e.g.,Soneco® or Röhnrad®, for approximately 20 minutes (10 rpm) to obtain thedesired final tabletting mixture.

[0151] c) Compression step

[0152] 18. The tabletting mixture from step 17 is pressed into tabletsusing compression pressures of 11, 14 or 17 KN on a rotary tablettingmachine, e.g., Fette®, Korsh®, Kelian® or Coarty® (temperature<20° C.;rH (relative humidity)<40%)

Example 2 Composition of a 2 Mg Tablet (1 Mg of Base Corresponds to1.385 Mg of the Hydrogen Maleate Salt of Compound A)

[0153] Compound A hml  2.77 (2 mg base) Polyplasdone XL USP/NF 36.00Glyceryl monostearate USP/NF  9.00 Poloxalkol  1.80 Lactose 200 mesh30.53 HPMC 3cPs  4.50 Polyethyleneglycol 4000  5.40 Water adsorbed  2.00Total 92 mg

Example 3

[0154] A 6 mg tablet formulation may be prepared by the manufacturingprocess described hereinafter.

[0155] a) Preparation of the granulated material

[0156] Preparation of the granulating solution

[0157] 1. Approximately 40 kg of purified water are weighed out.

[0158] 2. 3.600 kg of methylhydroxypropylcellulose 3 maps are added tothe purified water from step 1 while stirring until dissolution.

[0159] 3. 1.440 kg of poloxamer 188 are added to the solution from step2 while stirring until dissolution (mixing tank under stirring).

[0160] Granulating step

[0161] 4. 4.787 kg of compound A hml and 28.800 kg of crospovidone,21.853 kg of lactose monohydrate and 4.320 kg of glyceryl monostearateare weighed out.

[0162] 5. The ingredients from step 4 are mixed with the intensivemixer, e.g., Colette Gral® 300 I or Fielder® (mixer speed setting: 1;chopper speed setting: 1) for approximately 2 minutes.

[0163] 6. The mixture from step 5 is wetted with the granulatingsolution from step 3 while mixing with the intensive mixer, e.g.,Colette Gral® 300 I or Fielder® (mixer speed setting: 1; chopper speedsetting: 0; pumping rate approximately 4 kg/minute) for approximately 12minutes.

[0164] 7. Approximately 2 kg of purified water are weighed out.

[0165] 8. The vessel from step 3 is rinsed with the purified water fromstep 7 and this is added to the mixture from step 6 while mixing.

[0166] 9. The mass is granulated by mixing with the intensive mixer,e.g., Colette Gral® 300 I or Fielder® (mixer speed setting: 1; chopperspeed setting: 1) for approximately 2.5 minutes.

[0167] Drying step

[0168] 10. The granulate from step 9 is dried in a fluidised air beddrier, e.g., Glatt® or Aeromatic®) for approximately 65 minutes (Inletair temperature approximately 70° C.) to reach the desired loss ondrying (LOD) for the tabletting mixture, i.e., until LOD≦4.4%.

[0169] 11. The granulate sized by sieving (0.8 millimetres) with anoscillating sieve granulator (Frewitt® or Erweka®)

[0170] 12. Steps 1 to 11 are repeated.

[0171] b) Preparation of the tabletting mixture

[0172] 13. 8.640 kg of polyethylene glycol 4000 and 5.760 kg of glycerylmonostearate are sieved with an oscillating sieve granulator, e.g.,Frewitt® or Erweka® (0.8 millimetres)

[0173] 14. The ingredients from step 13 are added to the total mass ofgranulated material and this is mixed with a free fall mixer, e.g.,Soneco® or Röhnrad®, for approximately 20 minutes (10 rpm) in thedesired final tabletting mixture.

[0174] c) Compression step

[0175] 15. The tabletting mixture from step 14 is pressed into tabletsusing compression pressures of 13, 16 or 19 KN on a rotary tablettingmachine, e.g., Fette®, Korsh®, Kelian® or Coarty® (temperature<20° C.,rH (relative humidity)<40%).

Example 4 Composition of a 6 Mg Tablet (1 Mg of Base Corresponds to1.385 Mg of Hydrogen Maleate of Compound A)

[0176] Compound A hml  8.31 (6 mg base) Polyplasdone XL USP/NF  50.00Glyceryl monostearate USP/NF  12.50 Poloxalkol  2.50 Lactose 200 mesh 37.94 HPMC 3cPs  6.25 Polyathyleneglycol 4000  7.50 Water adsorbed 3.00 Total 128 mg

Example 5

[0177] A 0.5 mg tablet formulation may be prepared by the manufacturingprocess described hereinafter.

[0178] a) Preparation of the granulated material

[0179] Premixing step

[0180] 1. 1.994 kg of compound A hml and 31.126 kg of lactosemonohydrate are mixed with an intensive mixer (Colette Gral® 300 I orFielder®); mixer speed setting: 1; chopper speed setting: 1) forapproximately 1.5 minutes, or with a free fall mixer (Turbula®, Soneco®or Röhnrad®)

[0181] 2. The premixture from step 1 is then sieved (oscillatinggranulator, e.g., Frewitt® or Erweka®; mesh size: 0.8 millimetres).

[0182] 3. The premixture is divided into two portions of 16.560 kg.

[0183] Preparation of the granulating solution

[0184] 4. Approximately 43 kg of purified water are weighed out.

[0185] 5. 3.600 kg of methylhydroxypropylcellulose 3 maps are added tothe purified water from step 4 and this is stirred until dissolution.

[0186] 6. 1.440 kg of poloxamer 188 are added to the solution from step5 while stirring until dissolution.

[0187] Granulating sted

[0188] 7. 28.800 kg of crospovidone, 10.080 kg of lactose monohydrateand 4.320 kg of glyceryl monostearate are weighed out.

[0189] 8. One portion of the premixture from step 3 is added to theexcipients from step 7 and this is mixed with the intensive mixer, e.g.,Colette Gral® 300 I or Fielder® (mixer speed setting: 1; chopper speedsetting: 1) for approximately 2 minutes.

[0190] 9. The mixture from step 8 is wetted with the granulatingsolution from step 6 while mixing with the intensive mixer, e.g.,Colette Gral® 300 I or Fielder® (mixer speed setting: 1; chopper speedsetting: 0; pumping rate approximately: 4 kg/minute) for approximately12 minutes.

[0191] 10. Approximately 2 kg of purified water are weighed out.

[0192] 11. The vessel from step 6 is rinsed with the purified water fromstep 10 and this is added to the mixture from step 9 while mixing.

[0193] 12. The mass is granulated by mixing with the intensive mixer,Colette Gral® 300 I or Fielder® (mixer speed setting: 1; chopper speedsetting: 1) for approximately 2.5 minutes.

[0194] Drying step

[0195] 13. The granulate from step 12 is dried in a fluidised air beddrier (e.g., Glatt® or Aeromatic®) for approximately 60 minutes (inletair temperature approximately 70° C.) to reach the required loss ondrying (LOD) for the tabletting mixture, i.e. until LOD≦4.5%.

[0196] 14. The granulate sized by sieving (0.8 millimetres) with anoscillating sieve granulator, e.g., Frewitt® or Erweka®.

[0197] 15. Steps 4 to 14 are repeated with the other portion of step 3.

[0198] b) Preparation of the tabletting mixture

[0199] 16. 8.640 kg of polyethylene glycol 4000 and 5.760 kg of glycerylmonostearate are sieved (oscillating granulator, e.g., Frewitt® orErweka®; mesh size: 0.8 millimetres)

[0200] 17. The ingredients from step 16 are added to the total mass ofgranulated material and this is mixed with a free fall mixer, e.g.,Soneco® or Röhnrad®, for approximately 20 minutes (10 rpm) to obtain thedesired final tabletting mixture.

[0201] c) Compression step

[0202] 18. The tabletting mixture from step 17 is pressed into tabletson a rotary tabletting machine, e.g., Fette®, Korsh®, Kelian® or Coarty®(temperature<20° C.; rH (relative humidity)<40%)

Example 6 Composition of a 0.5 Mg Tablet (1 Mg of Base Corresponds to1.385 Mg of the Hydrogen Maleate Salt of Compound A)

[0203] Compound A hml  0.6925 (0.5 mg base) Polyplasdone XL USP/NF 20.00Glyceryl monostearate USP/NF  5.00 Poloxalkol  1.00 Lactose 200 mesh17.8075 HPMC 3cPs  2.50 Polyethyleneglycol 4000  3.00 Water adsorbed 1.00 Total 51 mg

Example 7 Composition of a 12 Mg Tablet (1 Mg of Base Corresponds to1.385 mg of the Hydrogen Maleate Salt of Compound A)

[0204] The manufacturing process is similar to the process used for the6 mg tablets. Compound A hml  16.62 (12 mg base) Polyplasdone XL USP/NF 72.00 Glyceryl monostearate USP/NF  18.00 Poloxalkol  3.60 Lactose 200mesh  49.98 HPMC 3cPs  9.0 Polyethyleneglycot 4000  10.8 Water adsorbed 4.00 Total 184 mg

1. A solid oral pharmaceutical composition comprising an effectiveamount of an acid sensitive active agent and a disintegrant which ispresent in an amount of at least 15% by weight based on the total weightof the composition.
 2. A solid oral pharmaceutical compositioncomprising an effective amount of an active agent which is poorlysoluble in aqueous media and a disintegrant which is present in anamount of at least 15% by weight based on the total weight of thecomposition.
 3. A pharmaceutical composition according to claim 1 or 2wherein the active agent has a solubility in aqueous media less than 1%.4. A pharmaceutical composition according to any of claims 1 to 3wherein the active agent is a serotonergic compound.
 5. A pharmaceuticalcomposition as claimed in any preceding claim wherein the active agentis a 5-HT₄ receptor antagonist.
 6. A pharmaceutical composition asclaimed in any of claims 1 to 4 wherein the active agent is a 5-HT₄receptor agonist.
 7. A pharmaceutical composition according to claim 6wherein the 5-HT₄ receptor agonist is Tegaserod, preferably its hydrogenmaleate (hml) salt.
 8. A pharmaceutical composition as claimed in anypreceding claim wherein the disintegrant is crospovidone.
 9. Apharmaceutical composition as claimed in any preceding claim comprisinga lubricant.
 10. A pharmaceutical composition according to claim 9wherein the lubricant comprises a glyceryl mono fatty acid.
 11. Apharmaceutical composition according to claim 9 wherein the lubricantcomprises a mixture of glyceryl monostearate and polyethylene glycol.12. A pharmaceutical composition as claimed in any preceding claimcomprising a surfactant.
 13. A pharmaceutical composition according toclaim 12 wherein the surfactant comprises poloxamer.
 14. Use of at least15% by weight of a disintegrant in the manufacturing of a solidpharmaceutical composition for the administering of an acid sensitiveactive agent.
 15. Use of at least 15% by weight of a disintegrant in themanufacturing of a solid pharmaceutical composition for theadministering of an active agent being acid sensitive and/or having apoor water solubility.
 16. Use according to claim 14 or 15 wherein theactive agent is a 5-HT₄ receptor agonist.
 17. Use according to claim 16wherein the 5-HT₄ receptor agonist is Tegaserod, preferably its hydrogenmaleate salt.
 18. Use of a pharmaceutical composition according to anyone. of claims 1 to 13 for the the manufacture of a composition for theprevention and treatment of gastro-intestinal motility disorders inhumans or animals.
 19. A process for improving dissolution properties ofa pharmaceutical composition as claimed in any of claims 1 to
 13. 20. Amethod for preventing, modulating or treating visceral pain ordiscomfort, for modulating visceral sensitivity or perception, forimproving sensory perception of rectal distension, or for treating analcontinence dysfunctions in a subject in need thereof, which methodcomprises administering to said subject an effective amount of a 5-HT₄receptor agonist, partial agonist or antagonist or a pharmaceuticallyacceptable salt thereof.
 21. A 5-HT₄ receptor agonist, partial agonistor antagonist or a pharmaceutically acceptable salt thereof for use inthe manufacture of a pharmaceutical composition for use in preventing,modulating or treating visceral pain or discomfort, modulating visceralsensitivity or perception, improving sensory perception of rectaldistension, or treating anal continence dysfunctions.
 22. Apharmaceutical composition for use in preventing, modulating or treatingvisceral pain or discomfort, modulating visceral sensitivity orperception, improving sensory perception of rectal distension, ortreating anal continence dysfunctions, which composition comprises a5-HT₄ receptor agonist, partial agonist or antagonist or apharmaceutically acceptable salt thereof, together with one or morepharmaceutically acceptable diluents or carriers therefor.
 23. A methodfor preventing or treating gastrointestinal motility disorders in horsesor cattle in need thereof, which method comprises administering to thehorses or cattle an effective amount of a 5-HT₄ receptor agonist orpartial agonist or a pharmaceutically acceptable salt thereof.
 24. A5-HT₄ receptor agonist or partial agonist or a pharmaceuticallyacceptable salt thereof, for use as a veterinary pharmaceutical or foruse in the manufacture of a veterinary pharmaceutical.
 25. Apharmaceutical composition for veterinary use comprising a 5-HT₄receptor agonist or partial agonist or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable diluent orcarrier therefor.
 26. A pharmaceutical composition comprising Tegaserodhaving dissolution characteristics in water or USP buffers pH 6.8 and7.5 of: time (minutes) amount (percentage) 5 30-90 15  80-100 30  95-10060 100